Method for making hydroxy-25-ene-vitamin D compounds

Details Method for making hydroxy-25-ene-vitamin D compounds Method for making hydroxy-25-ene-vitamin D compounds

2000-11-20

2002-08-27

Qazi, Sabiha (Department: 1617)

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C552S653000

Reexamination Certificate

active

06441207

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention related generally to vitamin D compounds and in particular, to vitamin D compounds in which the C-25 or equivalent position is double bonded, and specifically to a method of making such compounds.
Vitamin D has long been established as having an important biological role in bone and mineral metabolism. For example, vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. It is also known that it is not vitamin D itself, but metabolites generated from it in vivo that are effective in regulating calcium metabolism. The discovery of active forms of vitamin D, (M. F. Holick et al., 68
Proc. Natl. Acad. Sci. USA,
803-804 (1971); G. Jones et al., 14
Biochemistry,
1250-1256 (1975), and other active vitamin D analogs (M. F. Holick et al., 180 Science 190-191 (1973); H. Y. Lam et al., 186
Science
1038-1040 (1974) caused much excitement and speculation about the usefulness of these vitamin D compounds in the treatment of bone depletive disorders.
Animal studies examining the effects of these active vitamin D compounds, particularly 1&agr;,25-dihydroxyvitamin D
3
, the hormonally active form of vitamin D
3
, suggested that such agents would be useful in restoring calcium balance. An early clinical study indicated that oral administration of 0.5 &mgr;g/day of 1&agr;,25-dihydroxyvitamin D
3
to a group of postmenopausal women improved intestinal calcium absorption as well as calcium balance in the women. On this basis, U.S. Pat. No. 4,225,596 (“'596 Patent”) described and claimed the use of 1&agr;,25-dihydroxyvitamin D
3
for increasing calcium absorption and retention, i.e., this compound is highly potent in stimulating intestinal calcium absorption as well as the resorption of calcium from bone (i.e., bone mobilization).
The best indicator of the efficacy of vitamin D compounds, however, in the prevention or treatment of depletive bone disorders, however, is bone itself rather than calcium absorption or calcium balance. More recent clinical data indicate that, at the dosage ranges taught in the '596 Patent, 1&agr;,25-dihydroxy-vitamin D
3
has, at best, modest efficacy in preventing or restoring loss of bone mass or bone mineral content (S. M. Ott and C. H. Chesnut, 110
Ann. Int. Med.
267-274 (1989); J. C. Gallagher et al., 113
Ann. Int. Med.
649-655 (1990); J. Aloia et al., 84
Amer. J. Med.
401-408 (1988)).
These clinical studies with 1&agr;,25-dihydroxyvitamin D
3
, and another conducted with 1&agr;-hydroxyvitamin D
3
(M. Shiraki et al., 32
Endocrinol. Japan
305-315 (1985)), indicate that the capacity of these two vitamin D compounds to restore lost bone mass or bone mineral content is dose-related. The studies also indicate, however, that, at the dosage ranges required for either compound to be truly effective, toxicity in the form of hyperclacemia and hypercalciuria becomes a major problem. Specifically, attempts to increase the amount of 1&agr;,25-dihydroxyvitamin D
3
above 0.5 &mgr;g/day have frequently resulted in toxicity. At dosage levels below 0.5 &mgr;g/day, no effects are observed on bone mass or mineral content. (See, G. F. Jensen et al., 16
Clin. Invest.
305-309 (1981)). Two &mgr;g/day of 1&agr;-hydroxyvitamin D
3
was found to have efficacy in increasing bone mass in patients exhibiting senile osteoporosis (O. H. Sorensen et al., 7
Clin. Endocrinol.
169S-175S (1977)). Data from clinical studies in Japan, a population that has low calcium intake, indicate that efficacy is found with 1&agr;-hydroxyvitamin D
3
when administered at 1 &mgr;g/day (M. Shiraki et al., 32
Endocrinol. Japan.
305-315 (1985); H. Orimo et al., 3
Bone and Mineral
47-52 (1987)). At 2 &mgr;g/day, however, toxicity with 1&agr;-hydroxyvitamin D
3
occurs in approximately 67 percent of the patients, and at 1 &mgr;g/day, this percentage is approximately 20 percent. Thus, the 1&agr;-hydroxylated vitamin D
3
compounds can produce dangerously elevated blood calcium levels due to their inherent calcemic activity.
Because of their toxicity, 1-hydroxylated vitamin D
3
compounds can only be administered in oral dosages that are, at best, modestly beneficial in preventing or treating loss of bone or bone mineral content. Indeed, Aloia recommends that alternative routes of administration be sought which might avoid the toxicity problems and allow higher dosage levels to be achieved. (J. Aloia et al., 84
Amer. J. Med.
401-408 (1988)). Despite reported toxicities of 1&agr;-hydroxyvitamin D
3
and 1&agr;,25-dihydroxyvitamin D
3
, these two compounds remain the drugs of choice for many bone depletive disease treatments and calcium metabolism disorders such as renal osteodystrophy, hypoparathyroidism, vitamin D-resistant rickets and osteoporosis.
These two drugs also remain the only approved forms of 1&agr;-hydroxylated vitamin D for treating or preventing hyperparathyroidism which occurs secondary to the renal disease, although both drugs are not currently approved in all major pharmaceutical markets.
More recently, in addition to vitamin D's role in regulating calcium homeostatis, other biological roles for vitamin D have come to light. Specific nuclear receptors for 1&agr;,25-dihydroxyvitamin D
3
have been found in cells from diverse organs not involved in calcium homeostasis. For example, Miller et al., 52
Cancer Res. (
1992) 515-520, have demonstrated biologically active, specific receptors for 1,&agr;25-dihydroxyvitamin D
3
in the human prostatic carcinoma cell line, LNCaP.
It has been also shown that certain vitamin D compounds and analogs are potent inhibitors of malignant cell proliferation and inducers/stimulators of cell differentiation. For example, U.S. Pat. No. 4,391,802 issued to Suda et al. discloses that 1&agr;-hydroxyvitamin D compounds, specifically 1&agr;,25-dihydroxyvitamin D
3
and 1&agr;-hydroxyvitamin D
3
, possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia. Additionally, Skowronski et al., 136
Endocrinology
20-26 (1995), have reported antiproliferative and differentiating actions of 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogs on prostate cancer cell lines.
Still other roles for vitamin D have been suggested in the modulation of the immune response (see, e.g., U.S. Pat. No. 4,749,710 issued to Truitt et al.; U.S. Pat. No. 5,559,107 issues to Gates et al., U.S. Pat. Nos. 5,540,919, 5,518,725 and 5,562,910 issued to Daynes et al.; U.S. Pat. No. 5,880,114 issued to DeLuca et al.) and the inflammatory response (see, e.g., U.S. Pat. No. 5,589,471 issued to Hansen et al.) as well as treatment of multiple sclerosis (see, U.S. Pat. No. 5,716,946 issued to DeLuca et al.).
Nonetheless, despite their activity in diverse biological functions the fact remains that at the levels required in vivo for effective use, e.g., as antileukemic agents, the known vitamin D compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of active vitamin D compounds such as 1&agr;,25-dihydroxyvitamin D
3
and other vitamin D
3
analogs is precluded, or severely limited, because of their equally high potency as agents affecting calcium metabolism, i.e., by the risk of hypercalcemia. Considering the diverse biological actions of vitamin D and its potential as a therapeutic agent, a need exists for compounds with greater specific activity and selectivity of action, e.g., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity than therapeutic amounts of the known compounds or analogs of vitamin D.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a method for preparing hydroxy-25-ene-vitamin D compounds. These compounds are considered of value as pharmaceuticals because of their vitamin D activity but low toxicity when compared to the known vitamin D compoun

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